Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.

CCR5 deficiency: Decreased neuronal resilience to oxidative stress and increased risk of vascular dementia.

INTRODUCTION: As the chemokine receptor5 (CCR5) may play a role in ischemia, we studied the links between CCR5 deficiency, the sensitivity of neurons to oxidative stress, and the development of dementia. METHODS: Logistic regression models with CCR5/apolipoprotein E (ApoE) polymorphisms were applied on a sample of 205 cognitively normal individuals and 189 dementia patients from Geneva. The impact of oxidative stress on Ccr5 expression and cell death was assessed in mice neurons. RESULTS: CCR5-Δ32 allele synergized with ApoEε4 as risk factor for dementia and specifically for dementia with a vascular component. We confirmed these results in an independent cohort from Italy (157 cognitively normal and 620 dementia). Carriers of the ApoEε4/CCR5-Δ32 genotype aged ≥80 years have an 11-fold greater risk of vascular-and-mixed dementia. Oxidative stress-induced cell death in Ccr5-/- mice neurons. DISCUSSION: We propose the vulnerability of CCR5-deficient neurons in response to oxidative stress as possible mechanisms contributing to dementia.

Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to C9orf72 Repeat Expansions.

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions.

Mutational Landscape of Alzheimer's Disease and Frontotemporal Dementia: Regional Variances in Northern, Central, and Southern Italy.

Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Autophagy Markers Are Altered in Alzheimer's Disease, Dementia with Lewy Bodies and Frontotemporal Dementia.

The accumulation of protein aggregates defines distinct, yet overlapping pathologies such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). In this study, we investigated ATG5, UBQLN2, ULK1, and LC3 concentrations in 66 brain specimens and 120 plasma samples from AD, DLB, FTD, and control subjects (CTRL). Protein concentration was measured with ELISA kits in temporal, frontal, and occipital cortex specimens of 32 AD, 10 DLB, 10 FTD, and 14 CTRL, and in plasma samples of 30 AD, 30 DLB, 30 FTD, and 30 CTRL. We found alterations in ATG5, UBQLN2, ULK1, and LC3 levels in patients; ATG5 and UBQLN2 levels were decreased in both brain specimens and plasma samples of patients compared to those of the CTRL, while LC3 levels were increased in the frontal cortex of DLB and FTD patients. In this study, we demonstrate alterations in different steps related to ATG5, UBQLN2, and LC3 autophagy pathways in DLB and FTD patients. Molecular alterations in the autophagic processes could play a role in a shared pathway involved in the pathogenesis of neurodegeneration, supporting the hypothesis of a common molecular mechanism underlying major neurodegenerative dementias and suggesting different potential therapeutic targets in the autophagy pathway for these disorders.

Italian, European, and international neuroinformatics efforts: An overview.

Neuroinformatics is a research field that focusses on software tools capable of identifying, analysing, modelling, organising and sharing multiscale neuroscience data. Neuroinformatics has exploded in the last two decades with the emergence of the Big Data phenomenon, characterised by the so-called 3Vs (volume, velocity and variety), which provided neuroscientists with an improved ability to acquire and process data faster and more cheaply thanks to technical improvements in clinical, genomic and radiological technologies. This situation has led to a 'data deluge', as neuroscientists can routinely collect more study data in a few days than they could in a year just a decade ago. To address this phenomenon, several neuroimaging-focussed neuroinformatics platforms have emerged, funded by national or transnational agencies, with the following goals: (i) development of tools for archiving and organising analytical data (XNAT, REDCap and LabKey); (ii) development of data-driven models evolving from reductionist approaches to multidimensional models (RIN, IVN, HBD, EuroPOND, E-DADS and GAAIN BRAIN); and (iii) development of e-infrastructures to provide sufficient computational power and storage resources (neuGRID, HBP-EBRAINS, LONI and CONP). Although the scenario is still fragmented, there are technological and economical attempts at both national and international levels to introduce high standards for open and Findable, Accessible, Interoperable and Reusable (FAIR) neuroscience worldwide.

Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study.

OBJECTIVE: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage. METHODS: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls. RESULTS: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. INTERPRETATION: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. ANN NEUROL 2022;91:33-47.

Data-driven staging of genetic frontotemporal dementia using multi-modal MRI.

Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high-dimensional large-scale population datasets to obtain individual scores of disease stage. We used cross-sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting-state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI-obtained disease scores to the estimated years to onset (age-mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre-dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data-driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.

Serum neurofilament light in professional soccer players: goal on safety.

BACKGROUND: Sports-related concussion (SRC) is a subset of mild traumatic brain injuries occurring in contact sports. Most people recover spontaneously, but in retired professional players, the risk for neurodegenerative diseases is increased. A biomarker, such as neurofilament light chains (NfL), would help to address this issue and demonstrate sports' safety. Assessing NfL in professional soccer players may be the best way to investigate if repetitive head-impact exposure in the typical lower and asymptomatic range is harmful. OBJECTIVE: To evaluate whether the NfL in serum is a sensitive biomarker to detect mild brain injury in professional soccer players. METHODS: Thirty-six soccer players belonging to a professional Italian team underwent serum NfL assessment using ultrasensitive single-molecule array technology. Sixteen healthy nonathletic controls were also enrolled. Differences between groups and changes over time, considering pre-season vs. season, were considered. RESULTS: Serum NfL concentrations were comparable in the soccer professional players (median [interquartile range], 6.44 pg/mL [4.60-8.27] and controls (6.50 pg/mL [5.26-7.04]), with a median difference of - 0.06 pg/mL (95% CI -1.36 to 1.18), p = 0.957. No significant differences according to players' role (goalkeeper, defender, midfielder or forward) or according to timing of sampling (pre-season vs. season) were found. CONCLUSIONS: These results suggest that professional soccer, even when played at the highest level of competition, may be considered safe. Future studies assessing serum NfL levels after soccer-related concussions should be carried out, to evaluate their usefulness as a return-to-play marker avoiding second impact syndrome.

Regulatory miRNAs in Cardiovascular and Alzheimer's Disease: A Focus on Copper.

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. It is involved in a number of vital biological processes encompassing respiration, blood cell line maturation, and immune responses. In recent years, the link between deregulation of miRNAs' functionality and the development of various pathologies as well as cardiovascular diseases (CVDs) has been extensively studied. Alzheimer's disease (AD) is the most common cause of dementia in the elderly with a complex disease etiology, and its link with Cu abnormalities is being increasingly studied. A direct interaction between COMMD1, a regulator of the Cu pathway, and hypoxia-inducible factor (HIF) HIF-1a does exist in ischemic injury, but little information has been collected on the role of Cu in hypoxia associated with AD thus far. The current review deals with this matter in an attempt to structurally discuss the link between miRNA expression and Cu dysregulation in AD and CVDs.

Pathological 25 kDa C-Terminal Fragments of TDP-43 Are Present in Lymphoblastoid Cell Lines and Extracellular Vesicles from Patients Affected by Frontotemporal Lobar Degeneration and Neuronal Ceroidolipofuscinosis Carrying a GRN Mutation.

Frontotemporal lobar degeneration (FTLD) is a complex disease, characterized by progressive degeneration of frontal and temporal lobes. Mutations in progranulin (GRN) gene have been found in up to 50% of patients with familial FTLD. Abnormal deposits of post-translationally-modified TAR DNA-binding protein of 43 kDa (TDP-43) represent one of the main hallmarks of the brain pathology. To investigate in peripheral cells the presence of the different TDP-43 forms, especially the toxic 25 kDa fragments, we analyzed lymphoblastoid cell lines (LCLs) and the derived extracellular vesicles (EVs) from patients carrying a GRN mutation, together with wild-type (WT) healthy controls. After characterizing EV sizes and concentrations by nanoparticle tracking analysis, we investigated the levels of different forms of the TDP-43 protein in LCLs and respective EVs by Western blot. Our results showed a trend of concentration decreasing in EVs derived from GRN-mutated LCLs, although not reaching statistical significance. A general increase in p-TDP-43 levels in GRN-mutated LCLs and EVs was observed. In particular, the toxic 25 kDa fragments of p-TDP-43 were only present in GRN-mutated LCLs and were absent in the WT controls. Furthermore, these fragments appeared to be more concentrated in EVs than in LCLs, suggesting a relevant role of EVs in spreading pathological molecules between cells.

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.

MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia.

INTRODUCTION: Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. METHODS: A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation. RESULTS: Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores. CONCLUSION: Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database.

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia.

INTRODUCTION: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). METHODS: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. RESULTS: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. DISCUSSION: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes.

INTRODUCTION: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. METHODS: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. RESULTS: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. DISCUSSION: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.

Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer's Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene.

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer's disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.

Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration.

OBJECTIVE: To assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau181 (p-Tau181) in a large cohort of patients with frontotemporal lobar degeneration (FTLD). METHODS: In this retrospective study, performed on 417 participants, we analysed serum NfL and p-Tau181 concentrations with an ultrasensitive single molecule array (Simoa) approach. We assessed the diagnostic values of serum biomarkers in the differential diagnosis between FTLD, Alzheimer's disease (AD) and healthy ageing; their role as markers of disease severity assessing the correlation with clinical variables, cross-sectional brain imaging and neurophysiological data; their role as prognostic markers, considering their ability to predict survival probability in FTLD. RESULTS: We observed significantly higher levels of serum NfL in patients with FTLD syndromes, compared with healthy controls, and lower levels of p-Tau181 compared with patients with AD. Serum NfL concentrations showed a high accuracy in discriminating between FTLD and healthy controls (area under the curve (AUC): 0.86, p<0.001), while serum p-Tau181 showed high accuracy in differentiating FTLD from patients with AD (AUC: 0.93, p<0.001). In FTLD, serum NfL levels correlated with measures of cognitive function, disease severity and behavioural disturbances and were associated with frontotemporal atrophy and indirect measures of GABAergic deficit. Moreover, serum NfL concentrations were identified as the best predictors of survival probability. CONCLUSIONS: The assessment of serum NfL and p-Tau181 may provide a comprehensive view of FTLD, aiding in the differential diagnosis, in staging disease severity and in defining survival probability.

Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration.

OBJECTIVES: The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers. METHODS: The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales. RESULTS: The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills. CONCLUSION: Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.